Research ArticleNeurodegenerative Disease

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

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Science Translational Medicine  12 Apr 2017:
Vol. 9, Issue 385, eaah5642
DOI: 10.1126/scitranslmed.aah5642

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Connecting the dots in neurodegenerative disease

Heterozygous GRN mutations lead to progranulin haploinsufficiency and cause frontotemporal dementia (FTD) in the elderly population, whereas homozygous GRN mutations cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease that mainly affects children. The underlying relationship between progranulin-deficient FTD and NCL remains unexplored. Now, Ward et al. show that patients with heterozygous GRN mutations exhibit clinical and pathological features that are strikingly similar to NCL. Like NCL patients, individuals with heterozygous GRN mutations accumulate storage material throughout the central nervous system, and their cells exhibit signs of lysosomal dysfunction. These findings implicate lysosomal dysfunction as a central mechanism in both GRN-associated FTD and NCL.

Abstract

Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

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